Resistance-size, myogenic arteries regulate both systemic blood pressure and regional flow. L-type voltage- dependent calcium (Ca2+, CaV1.2) channels are the primary Ca2+ entry pathway in myocytes of resistance-size arteries and regulate physiological functions including contractility and gene expression. CaV1.2 channels are formed from multiple subunits, including a pore forming 11 and an auxiliary 124 and 2 which modulate channel properties. Despite the importance of vascular CaV1.2 channels, little is known regarding the functional significance of myocyte splice variants and auxiliary subunits. In hypertension there is an increase in arterial myocyte Cav1.2 currents, leading to an elevation in vascular contraction and blood pressure, but mechanisms mediating this pathological alteration are unclear. Similarly, there are few approaches to selectively target Cav1.2 channels to reduce vascular contractility. This proposal stems from preliminary data which suggest that myocytes of resistance-size cerebral arteries express a novel CaV1.2 11 subunit splice variant that is uniquely modulated by the auxiliary 124 subunit. Data also indicate that in hypertension, altered myocyte Cav1.2 channel regulation by 124 leads to an elevation in Cav1.2 currents and vasoconstriction. The overall goal of this application is to expand our knowledge of the molecular physiology of CaV1.2 channels in myocytes of resistance-size cerebral arteries and to study functional alterations that are associated with hypertension.
Three specific aims will be investigated.
Aim 1 will examine arterial myocyte CaV1.2 11 subunit splice variants in normotension and hypertension and test the hypothesis that molecular targeting of a myocyte-specific N-terminal variant causes vasodilation.
Aim 2 will investigate the hypothesis that 124 modulates myocyte CaV1.2 currents and that hypertension is associated with altered regulation, leading to a Cav1.2 current elevation and vasoconstriction.
Aim 3 will explore the hypothesis that in arterial myocytes, 124 is necessary for plasma membrane insertion of CaV1.2 11 subunits and that upregulation in hypertension leads to vasoconstriction. To investigate these aims, we will use a wide variety of techniques, including quantitative polymerase chain reaction, patch-clamp electrophysiology, laser-scanning confocal microscopy, Western blotting, RNA interference, intracellular Ca2+ measurements, and pressurized arterial diameter myography. These studies will improve knowledge of the molecular identity, subunit regulation, physiology, and pathophysiology of CaV1.2 channels that are expressed in myocytes of resistance-size arteries.

Public Health Relevance

Project Narrative Voltage-dependent calcium (Ca2+) channels of the CaV1.2 family are the principal Ca2+ influx pathway in arterial smooth muscle cells, regulate a variety of physiological functions including contractility, and are upregulated in hypertension leading to vasoconstriction and elevated blood pressure. The molecular identity and associated functions of CaV1.2 channel subunits that are expressed in smooth muscle cells of arteries that regulate blood pressure and flow in normotension and hypertension is poorly understood. Our proposal will investigate the hypothesis that molecularly distinct CaV1.2 channels are expressed in arterial smooth muscle cells, and that the molecular composition of these channels is altered in hypertension, leading to vasoconstriction.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Vascular Cell and Molecular Biology Study Section (VCMB)
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OH, Youngsuk
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University of Tennessee Health Science Center
Schools of Medicine
United States
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Kidd, Michael W; Bulley, Simon; Jaggar, Jonathan H (2017) Angiotensin II reduces the surface abundance of KV 1.5 channels in arterial myocytes to stimulate vasoconstriction. J Physiol 595:1607-1618
Samak, Geetha; Gangwar, Ruchika; Meena, Avtar S et al. (2016) Calcium Channels and Oxidative Stress Mediate a Synergistic Disruption of Tight Junctions by Ethanol and Acetaldehyde in Caco-2 Cell Monolayers. Sci Rep 6:38899
Sullivan, Michelle N; Gonzales, Albert L; Pires, Paulo W et al. (2015) Localized TRPA1 channel Ca2+ signals stimulated by reactive oxygen species promote cerebral artery dilation. Sci Signal 8:ra2
Leo, M Dennis; Bulley, Simon; Bannister, John P et al. (2015) Angiotensin II stimulates internalization and degradation of arterial myocyte plasma membrane BK channels to induce vasoconstriction. Am J Physiol Cell Physiol 309:C392-402
Burris, Sarah K; Wang, Qian; Bulley, Simon et al. (2015) 9-Phenanthrol inhibits recombinant and arterial myocyte TMEM16A channels. Br J Pharmacol 172:2459-68
Kidd, Michael W; Leo, M Dennis; Bannister, John P et al. (2015) Intravascular pressure enhances the abundance of functional Kv1.5 channels at the surface of arterial smooth muscle cells. Sci Signal 8:ra83
Peixoto-Neves, Dieniffer; Leal-Cardoso, Jose Henrique; Jaggar, Jonathan H (2014) Eugenol dilates rat cerebral arteries by inhibiting smooth muscle cell voltage-dependent calcium channels. J Cardiovasc Pharmacol 64:401-6
Leo, M Dennis; Bannister, John P; Narayanan, Damodaran et al. (2014) Dynamic regulation of ?1 subunit trafficking controls vascular contractility. Proc Natl Acad Sci U S A 111:2361-6
Bulley, Simon; Jaggar, Jonathan H (2014) Cl? channels in smooth muscle cells. Pflugers Arch 466:861-72
Narayanan, Damodaran; Bulley, Simon; Leo, M Dennis et al. (2013) Smooth muscle cell transient receptor potential polycystin-2 (TRPP2) channels contribute to the myogenic response in cerebral arteries. J Physiol 591:5031-46

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